5
Headache Medicine, v.10, n.1, p.5-9, 2019
ABSTRACT
RESUMO
Descritores: Enxaqueca; Migrânea; Warfarina; Acenocoumarol; Vitamina K;
Trombina
VIEWS AND REVIEWS
Systematic review of the benecial effects of thrombin
and vitamin K inhibitors on migraine treatment
Revisão sistemática dos efeitos benécos dos inibidores de
trombina e de vitamina K no tratamento da enxaqueca
Eduardo de Almeida Guimaraes
Nogueira
1
Angela dos Anjos Couto
2
Beatriz Moraes Grossi
2
Gabriela Dias Nunes
2
Taliê Zanchetta B. Hanada
2
Yara Dadalti Fragoso
1
1
MS & Headache Research, Santos, SP, Brazil
2
Department of Neurology, Medical School,
UNIMES. Medical students, Universidade
Metropolitana de Santos, Santos, SP
*Correspondence
Yara Dadalti Fragoso
E-mail: yara@bsnet.com.br
Received: November 24, 2018.
Accepted: January 30, 2019.
Background: Prophylactic migraine therapy includes beta-blockers,
anticonvulsants, tricyclic antidepressants and calcium channel modulators.
These drugs have been serendipitously identied as agents capable of
migraine control. In order to reduce drug intake, interactions and potential
adverse events, patients who have high blood pressure and migraine are
often prescribed beta-blockers or calcium channel antagonists. Patients with
epilepsy and migraine can use anticonvulsants, those with depression and
migraine can be treat with antidepressants, and those with heart arrhythmia
or recurrent vertigo and concomitant migraine can benet from use of calcium
channel antagonists. The benecial effects of vitamin K or thrombin inhibitors
on migraine attacks were rst described decades ago, and there may be a place
for these drugs in migraine prophylaxis. Objective: To investigate the potential
benecial effects of this class of anticoagulants regarding prevention of
migraine attacks. Method: Systematic review of the literature including papers
with patients’ results. Results: A search of the literature yielded 16 papers with
data on patients using inhibitors of vitamin K or thrombin for thromboembolic
conditions. Articles typically reported on single cases or small case series. In all
but one of these reports, the effect of the drug was remarkable in decreasing
migraine severity. Conclusion: Although the level of recommendation is low
due to the lack of proper clinical trials, vitamin K or thrombin inhibitors may be
useful for migraine management in patients who also require anticoagulation.
For these individuals, use of this class of anticoagulants could avoid adding
extra drugs for migraine management.
Keywords: Vitamin K, Migraine, Treatment
Introdução: O tratamento prolático da enxaqueca inclui betabloqueadores,
anticonvulsivantes, antidepressivos tricíclicos e modulares dos canais de cálcio.
Estas drogas foram identicadas de forma casual como agentes capazes de
controlar enxaqueca. Os efeitos benécos dos inibidores da vitamina K ou da
trombina na prevenção de crises de enxaqueca foi inicialmente descrito há
muitas décadas, podendo haver lugar para estas medicações na prolaxia. O
objetivo desta revisão foi a investigação dos potenciais efeitos benécos desta
classe de anticoagulantes como preventivos de crises de enxaqueca. Método:
Revisão sistemática da literatura usando como termos de busca “heparin” OR
“warfarin” OR “coumarol” OR “thrombin” AND “migraine” nas seguintes bases
de dados: Medline, PubMed, LILACS, SciELO e Google Scholar. Resultados: A
busca sistemática resultou em 16 artigos com dados sobre pacientes que usavam
inibidores da vitamina K ou da trombina para condições tromboembólicas.
Os artigos relataram casos isolados ou pequenas séries de casos. Em todos,
exceto um artigo, o efeito destas drogas foi ótimo na redução da gravidade
da enxaqueca. Conclusão: Embora o nível de recomendação seja baixo pela
falta de estudos clínicos apropriados, inibidores da vitamina K ou da trombina
podem ser úteis no controle da enxaqueca de pacientes que necessitam
anticoagulação. Para estas pessoas, o uso desta classe de anticoagulantes
poderia evitar a adição de drogas extras para o controle da enxaqueca.
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Vitamin K inhibitors in migraine treatment
Nogueira EAG, et al.
Headache Medicine, v.10, n.1, p.5-9, 2019
6
INTRODUCTION
Migraine is a common neurological disorder
characterized by episodic attacks and by a chronic
phase, both of which can be disabling.
1
In addition to
cortical, thalamic and hypothalamic dysfunction, the
cascade of reactions led by the trigeminovascular
system requires adequate management and therapeutic
interventions.
1
In subjects who do not tolerate or do not
respond well to acute treatments, continuous use of a
prophylactic drug is the best option. Interestingly, these
prophylactic agents have mostly been identied by
chance: while undergoing treatment for another disease
with a certain drug, patients reported reduced numbers
and lower intensity of migraine attacks. Beta-blockers,
anticonvulsants, tricyclic antidepressants and calcium
channel modulators have all been identied as potential
prophylactic therapies for migraine. These are now
approved and recommended for migraine prevention,
with evidence supporting their use.
2
It is only logical that patients who can benet from
the same drug to treat two diseases should receive
this drug when they have no contraindication for this
minimalistic approach. Therefore, patients who have
high blood pressure and migraine can benet from
beta-blockers or calcium channel antagonists, and those
with epilepsy and migraine can use anticonvulsants.
Likewise, individuals with depression and migraine can
be treat with antidepressants, while subjects with heart
arrhythmia or recurrent vertigo and concomitant migraine
can benet from use of calcium channel antagonists.
Following the same line of thought, migraineurs
requiring anticoagulation can benet from vitamin K or
thrombin inhibitors, according to the theory and results
presented in papers published over the last 55 years.
Following an initial investigation on the potential role
of basophil granulocytes in migraine.
3
heparin became
a matter of interest in the physiopathology of migraine
attacks. Thonnard-Neumann published a series of papers
discussing the potential role of heparin in migraine
4, 5
after
an initial case-control open trial.
6
Other papers followed
but the subject is yet far from clear. The objective of the
present review was to assess the potential benecial
effects of this class of anticoagulants on prevention of
migraine attacks.
METHOD
This study was a systematic review and did not
require approval from an Ethics Committee, since the
authors only accessed published data. The present review
followed the guidelines of the
Preferred Reporting Items
for Systematic Review and Meta-Analysis
(PRISMA)
protocol.
7
The search terms were “heparin” OR “warfarin”
OR “coumarol” OR “thrombin” AND “migraine” in
the following databases: Medline, PubMed, LILACS,
SciELO and Google Scholar. The term “headache” as
an alternative to “migraine” generated thousands of
unrelated papers and was, therefore, not used in the
search. The search was not limited by date and only
papers presenting data on patients were selected. Only
articles that used the English language in title, key words
and abstract were included. Abstracts from conferences
and journal editorials were not included in this review.
References from selected articles were further used in
the search for other potential papers.
The authors individually searched for papers
following the set criteria for inclusion and exclusion
and, after two meetings, decided which articles should
be included. The results from this systematic review are
presented essentially in descriptive form with no meta-
analyses or statistical assessment of the results.
RESULTS
The initial search generated 163 papers. After reading
the titles of these papers and their abstracts, 16 articles
were selected for this review. One article, published in
1974
8
had no authors listed and no abstract. It could not
be retrieved and was, therefore, excluded, despite its
potential interesting title. One case report from Sweden
9
was also excluded, although it had been identied as a
reference to other authors. This paper is in Swedish and
the search in the original journal rendered no results for
that particular article.
There were 11 case reports from eight different
countries (UK,
10
, Holland,
11, 12
Brazil,
13
South Africa,
14
Italy,
15-17
Taiwan,
18
Canada,
19
USA
20
), one retrospective cohort from
Holland,
21
one prospective cohort (from USA),
22
one open
crossover trial from Holland,
23
two case control studies
(USA,
4
Spain,
24
). Data were typically obtained from
isolated cases or small series of patients. The results from
15 studies suggested that heparin, warfarin and coumarin
derivatives can be very effective in reducing the intensity
and/or frequency of migraine attacks. One of the studies
did not obtain the same good result when comparing
acenocoumarol to propranolol in migraine prophylaxis.
23
An International Normalized Ratio (INR) of around 2.5
was sufcient to induce improvement in migraine, thus
indicating that full anticoagulation is not necessary to
alleviate the headache. A summary of the papers with
data on patients is presented in Table 1.
DISCUSSION
Serendipitous discoveries have been a characteristic
of many drugs used in migraine prophylaxis. The present
review showed that potent anticoagulants that are vitamin
K inhibitors have shown remarkable benecial effects in
migraineurs. All studies have the same conclusion and it
would be of great interest to prospectively study large
cohorts of patients (who happen to have migraine) and
need to be treated with vitamin K inhibitors.
Thrombin is a serine protease involved in a cascade
of coagulation and inammation via the proteinase-
activated receptors (PARs).
25
Pro-inammatory
mediators are released through activation of PAR1, while
the activation of PAR2 induces the release of substance
P and calcitonin-gene-related peptide (CGRP).
26-28
The
aberrant activity of serine proteases, including thrombin,
can be identied in many neurological conditions,
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Nogueira EAG, et al.
7
Headache Medicine, v.10, n.1, p.5-9, 2019
Author Year Ref Country Method Result
Thonnard-
Neumann
1973 4 USA
Case-control (n=20 migraine;
21 control)
5,000 U of heparin intravenously leading to a
substantial reduction in severity and frequency of
migraine attacks in 16 out of 20 migraine patients.
Suresh et al 1994 10 UK Case report (n=1)
6mg/day warfarin prescribed to a 71 year-
old woman (DVT) led to migraine control.
Withdrawal resulted in migraine returning to
basaline pattern. Patient was treated blindly
with warfarin-placebo and only warfarin
improved her headache attacks
van
Puijenbroek
1996 11 Holland Case report (n=1)
3-4mg/day acenocoumarol led to a dramatic
reduction of migraine attacks in a 68 year-old
woman. Migraines returned after drug was
withdrawn and was well controlled again after
re-starting acenocoumarol
Fragoso 1997 13 Brazil Case report (n=2)
Two patients with remarkable improvement
on the intensity and frequency of their
migraine attacks after taking 5mg/day of
warfarin (INR kept at 2.5).
Morales-
Asin et al
2000 24 Spain
Case-control (66 migraine; 100
non-migraine headache)
Remarkable improvement on migraine during
the use of acenocoumarol. More severe
migraine had better response to this treatment
Rahimtoola
et al
2001 21 Holland
Retrospective analyses (n=32
warfarin; n=60 aspirin)
Coumarin treatment was clearly associated with
a reduction of migraine attacks and severity in
comparison with low-dose aspirin treatment
Wammes-
van der
Heijden et al
2004 12 Holland Case report (n=4)
Patients with migraine and thromboembolic
predisposition improved of their headache
during acenocoumarol therapy
Wammes-
van der
Heijden et al
2005 23 Holland
Open crossover study using
propranolol or acenocoumarol
(n=12)
No beneficial effect of propranolol or
acenocoumarol could be established after 12 weeks
Asherson
et al
2007 14 South Africa Case report (n=1)
Patient with anti-phospholipid syndrome
undergoing therapy with warfarin had
dramatic improvement in migraine
Maggioni
et al
2012 15 Italy Case report (n=1)
Complete remission of migraine in a woman
undergoing warfarin therapy. Migraines
returned after drug was withdrawn and was
well controlled again after re-starting warfarin
Russo et al 2013 16 Italy Case report (n=1)
Patient undergoing therapy with warfarin
had total remission of migraine pain but
remained with aura
Mohanty
et al
2015 22 USA
Prospective (n=40 migraine;
n=85 control)
Migraine symptoms substantially decreased in
38 patients using warfarin
Kung et al 2015 18 Taiwan Case report (n=1)
Dabigratan 110mg twice a day controlled
migraine-like visual aura without headache
Maggioni
et al
2015 17 Italy Case report (n=1)
Complete remission of migraine with aura on
warfarin. Return of symptoms within 3 weeks of
switching to apixaban. Resolution of symptoms
once again when warfarin was reintroduced
Nilsson et al 2017 19 Canada Case report (n=1)
Complete remission of migraine with aura on
warfarin. Return of symptoms within 3 weeks of
switching to apixaban. Resolution of symptoms
once again when warfarin was reintroduced
Beh 2018 20 USA Case report (n=1)
Patient with vestibular migraine who
improved when warfarin was associated to
his previous topiramate therapy
Table 1. Summarized results from articles reported on migraine patients using vitamin K or thrombin inhibitors.
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Headache Medicine, v.10, n.1, p.5-9, 2019
8
including hemorrhagic, hypoxic, oncogenic, traumatic
and infectious injuries.
29
Expressed in astrocytes,
microglia and neurons, PAR1 has been described as a
well-positioned receptor to play a central role mediating
the complex inammatory cascades within the central
nervous system,
29,30
It is, therefore, perfectly plausible
that thrombin might be involved in the inammatory
trigeminovascular cascade of events in migraine.
This review is not without limitations. The results
are essentially based on case reports with the bias of
publication of positive results. There may be migraineurs
with no benet at all from these drugs whose cases
are never going to be reported. Even the larger series
of patients and the prospective cohort identied by the
reviewers typically reported on insufcient numbers
of cases assessed in open studies. At present, it is only
possible to give a low (Code C) or very low (Code
D) recommendation for this therapy as a migraine
prophylactic alternative. As a reminder, Code C means
that there are only a few studies with severe limitations,
while Code D, in essence, denotes a recommendation
from experts.
31
In order to improve the personal and societal
impact of migraine, patients need to receive appropriate
treatments and continuity of care.
32
Adherence to therapy
is of essence and the fewer the numbers of drugs and
daily doses a patient has to use, the higher the chances
are that he/she will follow medical recommendations.
33,34
Patients who suffer from migraine and require
anticoagulant therapy for any other reason might achieve
improvement of their migraine through use of vitamin
K and thrombin inhibitors, even when the target INR is
relatively low. However, this recommendation is limited
by the low level of evidence presented by the data in
the medical literature. Prospective observational cohorts
among patients who suffer from migraine and receive
anticoagulant therapy for any other disease could be the
next step in this investigation.
CONCLUSION
The present systematic review showed that vitamin
K or thrombin inhibitors have a potential benecial
effect regarding prevention of migraine attacks. Careful
interpretation of the results is recommended since most
published data come from small series or single cases.
Role of authors:
Eduardo de Almeida Guimaraes Nogueira – recently
graduated medical doctor, coordinated the study and
prepared the nal table of results.
Angela dos Anjos Couto - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Beatriz Moraes Grossi - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Gabriela Dias Nunes - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Taliê Zanchetta B. Hanada - medical student in
training for systematic reviews, had an active participation
in the literature search and selection of papers
Yara Dadalti Fragoso - designed and supervised the
study, wrote the nal paper and is ultimately responsible
for data collection and analyses.
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